PROJECT SUMMARY/ ABSTRACT Individuals with Type 2 Diabetes Mellitus (T2DM), a chronic and progressive disease affecting over 26 million Americans, are at significantly higher risk for Alzheimer?s disease. Alzheimer?s disease is a serious health issue, afflicts over 5.5 million Americans with $259 billion in healthcare costs, and accounts for 70% of all dementia. The condition is characterized by cognitive deficits in several domains, and accompanied by frequent comorbid psychiatric conditions, with significantly reduced life expectancy after diagnosis. Both T2DM and Alzheimer?s disease conditions are connected at epidemiological, clinical, molecular, and brain function levels, but it is unclear why some T2DM patients are more susceptible to develop Alzheimer?s disease. T2DM patients also perform poorly on multiple cognitive domains, as Alzheimer?s disease patients. Multiple autopsy studies in T2DM are inconsistent with relationships to Alzheimer?s disease pathology, including amyloid plaque burden, a neurotoxic protein that promotes neurodegeneration, and suggest glycemic control can play a crucial role. Also, Alzheimer?s disease has a genetic component, with APOE genotype influencing the trajectory of Alzheimer?s disease in humans, with APOE ?4 genotype having more risk over others, which may be additive in T2DM patients. Also, both T2DM and Alzheimer?s disease conditions show brain tissue changes in multiple brain sites, with consistent global brain and hippocampal tissue changes, supporting the use of crucial imaging biomarkers for Alzheimer?s disease. Thus, poor glycemic control, genetic risk factors, brain beta amyloid deposition, and global brain and hippocampal tissue integrity can be considered as key Alzheimer?s disease biomarkers in T2DM. Using a one group longitudinal study design, several Alzheimer?s disease biomarkers, including global brain atrophy and hippocampal tissue changes, beta amyloid, glycemic control, and APOE genotype will be examined in 22 T2DM patients with cognitive deficits. Therefore, the specific aims are to: 1) compare global brain atrophy and hippocampal brain volume and tissue integrity, using MRI procedures, in T2DM patients with cognitive deficits at baseline, at 6-, and 9-months; and 2) examine beta amyloid and hemoglobin A1C levels at baseline, 6-, and 9-months, and APOE genotype at baseline in T2DM patients with cognitive deficits. In summary, T2DM patients are at higher risk for Alzheimer?s disease, which may result from several risk factors, including uncontrolled hyperglycemia, APOE ?4 genotype, and beta amyloid deposition. However, it is unknown why some T2DM patients are more prone to develop Alzheimer?s disease. Multiple biomarkers will be examined over time, which will indicate factors that may contribute to Alzheimer?s disease in T2DM patients. The findings could impact clinical practice of T2DM patients through the identification of potential patients that may develop Alzheimer?s disease with time, which will help in developing management strategies for these patients, and thus, improve T2DM self-care, quality of life, and other health outcomes in this high-risk patient population.